β-amino acids have been isolated in free form and show useful pharmacological properties. For example, β-amino acids can be cyclized to β-lactams, a well-known class of potential biologically active substances. These types of compounds are also excellent building blocks for the preparation of multiple natural products and have been shown to be useful tools in the synthesis of modified peptides with increased activity and in vivo stability.
Steer et al., in The Use of β-amino Acids in the Design of Protease and Peptidase Inhibitors, report that a peptidomimetic approach with significant potential has emerged in recent years that utilizes β-amino acids. The one important feature of β-amino acids is reported to be their biological stability. The biological stability is reported to be due to the fact that while β-amino acids, which have a similarity to α-amino acids in that they contain an amino terminus and a carboxyl terminus, also have two carbon atoms which separate these functional termini. As such, β-amino acids with a specific side chain can exist as the R or S isomers at either the α (C2) carbon or the β (C3) carbon resulting in a total of four possible isomers for any given side chain. This demonstrates that many more isomers are available in β-amino acids than is possible for the corresponding α-amino acids. Steer, David L.; Lew, Rebecca A.; Perlmutter, Patrick; Smith, A. Ian; Aguilar, Marie-Isabel; Letters in Peptide Science (2002), Volume Date 2001, 8(3–5), 241–246.
In β-Amino Acids: Versatile Peptidomimetics, Steer et al. review the use of β-amino acids in the design and synthesis of biologically active peptide analogues. They disclose that β-amino acids in the design of bioactive peptide analogues are rapidly expanding. The incorporation of β-amino acids is noted to be successful in creating peptidomimetics that not only have potent biological activity, but that are also resistant to proteolysis. Steer, David L.; Lew, Rebecca A.; Perlmutter, Patrick; Smith, A. Ian; Aguilar, Marie-Isabel. Current Medicinal Chemistry (2002), 9(8), 811–822.
Several methods for the preparation of enantiopure β-amino acids and their derivatives already exist. Among these methods, the conjugate addition of amines to unsaturated nitrites or esters followed by hydrolysis is useful due to raw material availability. Although this addition reaction results in high yield processes for the formation of racemic β-amino acids, most attempts to control the stereochemistry of the chiral center result in low yields and poor enantiomeric excess.
Considering the low cost of preparing racemic mixtures of β-amino alkylnitriles, resolution of these racemic substrates presents an excellent opportunity to develop a low cost process for the synthesis of optically active β-amino alkylnitriles and their corresponding β-amino acids as building blocks for making useful pharmaceutical compounds. However, little if any effort in this area appears in the scientific literature. Thus, there exists a need in the art for an efficient, low cost process for resolving racemic β-amino alkylnitriles.